Although the etiology of amyotrophic lateral sclerosis (ALS), an often fatal neurodegenerative disease, is still largely unexplained, research suggests that lead exposure may be a risk factor. Freya Kamel of the NIEHS earlier led a group that identified a potential role of lead exposure in the etiology of ALS. Now she and her colleagues have taken that work a step further, examining the possible association of ALS risk with specific genetic polymorphisms known to affect lead toxicokinetics [EHP 111:1335-1339].

The researchers used data from a case-control study conducted in New England between 1993 and 1996 that involved more than 100 ALS patients and 38 control subjects. The study participants completed questionnaires on demographic and lifestyle characteristics, and were invited to provide tissue samples for measurement of blood and bone lead concentrations. For this analysis, DNA genotyping was performed using blood samples from the original study.

In many adults with no known recent environmental exposure (including most of the subjects in the study), internal lead exposure--that is, the migration of stored lead from bone into the blood--is the major source of blood lead. The researchers speculated that polymorphisms of two genes--ALAD (which codes for [delta]-aminolevulinic acid dehydratase, an enzyme involved in heme synthesis in red blood cells) and VDR (which codes for the vitamin D receptor)--might confer increased susceptibility to ALS through their previously confirmed impact on lead retention or mobilization in bone and blood.

Kamel and colleagues found that the variant allele (ALAD 2) of the polymorphism denoted as ALAD K59N was positively associated with an approximate twofold increase in risk of ALS after adjustment for age, sex, region, education, and physical activity. In the course of their analysis, they also identified a previously unknown polymorphism, denoted as ALAD IVS2+299G>A. The variant allele of that polymorphism (ALAD I2-2) was found, after similar adjustment, to be negatively associated with ALS risk. Both alleles were positively associated with decreased bone lead concentrations, and neither affected the relationship of blood or bone lead to ALS. No ALS risk associations were found with the alleles of the VDR polymorphism, nor did it appear to be associated with blood or bone lead concentrations.

The researchers theorize that although ALAD alleles did not modify the relationship of ALS to lead in this cross-sectional study, genetic susceptibility conferred by these polymorphisms might still affect risk through a mechanism related to internal lead exposure. ALAD 2 appears to promote retention of lead in blood and migration of lead from bone to blood. The current findings are consistent with the hypothesis that this increased retention of lead in blood relative to bone increases its availability to target tissues and hence its toxicity. The authors speculate that "alterations in lead toxicokinetics conferred by the presence of the ALAD 2 allele may subtly increase exposure to lead throughout a person's lifetime, thereby elevating risk."

The authors point out that the study is limited by a low participation rate of control subjects (41%) in providing tissue samples, although a much higher percentage completed the questionnaire, leading to concerns about selection bias and contributing to imprecision in the statistical evaluation of relationships. They conclude that because the study is small and the observation unique, further research is necessary to confirm or refute the hypothesis. Considering that the frequency of the ALAD 2 allele is approximately 10% in Caucasian populations, if this study's conclusions are confirmed, it will be an important contribution to identifying a large number of people who could be at elevated risk for developing a devastating, incurable disease.

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